# New mechanisms of SERCA2a regulation: role of luminal calcium

> **NIH NIH R01** · LOYOLA UNIVERSITY CHICAGO · 2022 · $434,456

## Abstract

PROJECT SUMMARY/ABSTRACT
SERCA2a Ca pump plays a central role in heart function. The speed at which SERCA2a removes Ca from the
cytosol is the main determinant of the rate of cardiac muscle relaxation. SERCA2a also sets the total amount of
Ca in the sarcoplasmic reticulum (SR), which determines the strength of cardiac contraction. It is not surprising,
that impaired SERCA2a function has been reported in a number of pathological conditions, including heart failure
(HF). Thus, understanding mechanisms of SERCA regulation is of great clinical importance. Besides activation
of muscle contraction, SR luminal Ca ([Ca]SR) plays an important role in regulation of SR protein function. While
SERCA2a activity controls [Ca]SR, less is known about how changes in [Ca]SR affect SERCA2a Ca transport. Our
preliminary results suggest that SR luminal Ca plays an important role in regulation of SERCA2a. In this project
we will use advanced structural analyses, innovative molecular biological techniques, new organelle-specific
sensors, state-of-the-art optical methods and in vivo gene delivery to explore this new mechanism of SERCA2a
regulation. In Aim 1, we will test the hypothesis that luminal Ca regulates SERCA2a by increasing the pump’s
catalytic efficacy and by relieving the phospholamban (PLB) inhibitory effect. Molecular dynamic simulations will
be used to select specific domains on the SERCA2a luminal side that are involved in Ca regulation. Site-directed
mutagenesis will be used to identify the specific amino acids that form the luminal Ca-binding sites and to develop
the luminal Ca-insensitive SERCA2a mutant. We will assess effects of the luminal Ca regulation on Ca transport,
the ATPase activity and the PLB interaction. Then, myocytes expressing the luminal Ca-insensitive SERCA2a
mutant will be studied to define the role of this novel mechanism in cardiac Ca cycling. We expect that the
outcome of this work will greatly advance our understanding of SERCA2a function. We expect that the outcome
of these studies will provide a detailed view of this new mechanism of SERCA2a regulation, advancing our
understanding of the Ca pump’s function. In Aim 2, we will test the hypothesis that luminal redox potential regulates
SERCA2a by stabilizing its luminal Ca binding sites, thus, improving the pump’s regulation by [Ca]SR. Molecular
dynamic simulations will be used to forecast the role of the SERCA2a luminal disulfide bond in the pump catalytic
cycle. We will assess whether mutation of luminal cysteines leads to a loss-of-function phenotype by abolishing
SERCA2a regulation by luminal Ca. Newly developed approaches to measure luminal redox potential and [Ca]SR
will be used to define the cross-talk between luminal redox potential and SERCA2a activity. We will investigate
the contribution of this new mechanism to SERCA2a dysfunction and Ca mishandling in HF. The likely outcome
of these studies is a new concept that can explain how alterations in SERCA2a structure/function...

## Key facts

- **NIH application ID:** 10348728
- **Project number:** 5R01HL151990-02
- **Recipient organization:** LOYOLA UNIVERSITY CHICAGO
- **Principal Investigator:** Aleksey V Zima
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $434,456
- **Award type:** 5
- **Project period:** 2021-02-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348728

## Citation

> US National Institutes of Health, RePORTER application 10348728, New mechanisms of SERCA2a regulation: role of luminal calcium (5R01HL151990-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10348728. Licensed CC0.

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